Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector

Article


Della Peruta, Marco, Badar, Adam, Rosales, Cecilia, Chokshi, Shilpa, Kia, Azadeh, Nathwani, Devhrut, Galante, E., Yan, Ran, Arstad, Erik, Davidoff, Andrew M., Williams, Roger, Lythgoe, Mark F. and Nathwani, Amit C. 2015. Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector. Human Gene Therapy. 26 (2), pp. 94-103. https://doi.org/10.1089/hum.2014.052
AuthorsDella Peruta, Marco, Badar, Adam, Rosales, Cecilia, Chokshi, Shilpa, Kia, Azadeh, Nathwani, Devhrut, Galante, E., Yan, Ran, Arstad, Erik, Davidoff, Andrew M., Williams, Roger, Lythgoe, Mark F. and Nathwani, Amit C.
Abstract

A novel selectively targeting gene delivery approach has been developed for advanced hepatocellular carcinoma (HCC), a leading cause of cancer mortality whose prognosis remains poor. We combine the strong liver tropism of serotype-8 capsid-pseudotyped adeno-associated viral vectors (AAV8) with a liver-specific promoter (HLP) and microRNA-122a (miR-122a)-mediated posttranscriptional regulation. Systemic administration of our AAV8 construct resulted in preferential transduction of the liver and encouragingly of HCC at heterotopic sites, a finding that could be exploited to target disseminated disease. Tumor selectivity was enhanced by inclusion of miR-122a-binding sequences (ssAAV8-HLP-TK-122aT4) in the expression cassette, resulting in abrogation of transgene expression in normal murine liver but not in HCC. Systemic administration of our tumor-selective vector encoding herpes simplex virus-thymidine kinase (TK) suicide gene resulted in a sevenfold reduction in HCC growth in a syngeneic murine model without toxicity. In summary, we have developed a systemically deliverable gene transfer approach that enables high-level expression of therapeutic genes in HCC but not normal tissues, thus improving the prospects of safe and effective treatment for advanced HCC.

JournalHuman Gene Therapy
Journal citation26 (2), pp. 94-103
ISSN1043-0342
Year2015
PublisherMary Ann Liebert, Inc., publishers
Digital Object Identifier (DOI)https://doi.org/10.1089/hum.2014.052
Web address (URL)https://doi.org/10.1089/hum.2014.052
Publication dates
Print08 Jan 2015
Publication process dates
Deposited18 Aug 2017
Accepted10 Nov 2014
Copyright information© Mary Ann Liebert Inc. 2017
Permalink -

https://repository.uel.ac.uk/item/85781

  • 127
    total views
  • 0
    total downloads
  • 1
    views this month
  • 0
    downloads this month

Export as

Related outputs

Simple and effective method for the extraction of silymarin from Silybum marianum (L.) gaertner seeds
Gilabadi, S., Stanyon, H., Brandao De Ceita, D., Pendry, B. A. and Galante, E. 2023. Simple and effective method for the extraction of silymarin from Silybum marianum (L.) gaertner seeds. Journal of Herbal Medicine. 37 (Art.100619). https://doi.org/10.1016/j.hermed.2022.100619
Cranberry (Vaccinium macrocarpon) as a prophylaxis for urinary tract infections in women: A systematic review with meta-analysis
Valente, J., Pendry, B. and Galante, E. 2022. Cranberry (Vaccinium macrocarpon) as a prophylaxis for urinary tract infections in women: A systematic review with meta-analysis. Journal of Herbal Medicine. 36 (Art. 100602). https://doi.org/10.1016/j.hermed.2022.100602
Novel nucleotide–calixarene conjugates via phosphoester linkage
Consoli, Grazia M.L., Granata, Giuseppe, Galante, E., Cunsolo, Francesca and Geraci, Corrada 2006. Novel nucleotide–calixarene conjugates via phosphoester linkage. Tetrahedron Letters. 47 (19), pp. 3245-3249. https://doi.org/10.1016/j.tetlet.2006.03.043
Hydroxycinnamic acid clustered by a calixarene platform: radical scavenging and antioxidant activity
Consoli, Grazia M.L., Galante, E., Daquino, Carmelo, Granata, Giuseppe, Cunsolo, Francesca and Geraci, Corrada 2006. Hydroxycinnamic acid clustered by a calixarene platform: radical scavenging and antioxidant activity. Tetrahedron Letters. 47 (37), pp. 6611-6614. https://doi.org/10.1016/j.tetlet.2006.07.021
Synthesis of water-soluble nucleotide-calixarene conjugates and preliminary investigation of their in vitro DNA replication inhibitory activity
Consoli, Grazia M.L., Granata, Giuseppe, Galante, E., Di Silvestro, Isabella, Salafia, Laura and Geraci, Corrada 2007. Synthesis of water-soluble nucleotide-calixarene conjugates and preliminary investigation of their in vitro DNA replication inhibitory activity. Tetrahedron. 63 (44), pp. 10758-10763. https://doi.org/10.1016/j.tet.2007.06.123
Calix[4]arene Decorated with Four Tn Antigen Glycomimetic Units and P3CS Immunoadjuvant: Synthesis, Characterization, and Anticancer Immunological Evaluation
Geraci, Corrada, Consoli, Grazia M. L., Galante, E., Bousquet, Ennio, Pappalardo, Maria and Spadaro, Angelo 2008. Calix[4]arene Decorated with Four Tn Antigen Glycomimetic Units and P3CS Immunoadjuvant: Synthesis, Characterization, and Anticancer Immunological Evaluation. Bioconjugate Chemistry. 19 (3), pp. 751-758. https://doi.org/10.1021/bc700411w
A sinapic acid–calix[4]arene hybrid selectively binds Pb2+ over Hg2+ and Cd2+
Sgarlata, Carmelo, Zito, Valeria, Arena, Giuseppe, Consoli, Grazia Maria Letizia, Galante, E. and Geraci, Corrada 2009. A sinapic acid–calix[4]arene hybrid selectively binds Pb2+ over Hg2+ and Cd2+. Polyhedron. 28 (2), pp. 343-348. https://doi.org/10.1016/j.poly.2008.10.068
Glycoclusters presenting lactose on calix[4]arene cores display trypanocidal activity
Galante, E., Geraci, Corrada, Sciuto, Sebastiano, Campo, Vanessa L., Carvalho, Ivone, Sesti-Costa, Renata, Guedes, Paulo M.M., Silva, João S., Hill, Lionel, Nepogodiev, Sergey A. and Field, Robert A. 2011. Glycoclusters presenting lactose on calix[4]arene cores display trypanocidal activity. Tetrahedron. 67 (33), pp. 5902-5912. https://doi.org/10.1016/j.tet.2011.06.065
A One-Pot Three-Component Radiochemical Reaction for Rapid Assembly of125I-Labeled Molecular Probes
Yan, Ran, Sander, Kerstin, Galante, E., Rajkumar, Vineeth, Badar, Adam, Robson, Mathew, El-Emir, Ethaar, Lythgoe, Mark F., Pedley, R. Barbara and Årstad, Erik 2012. A One-Pot Three-Component Radiochemical Reaction for Rapid Assembly of125I-Labeled Molecular Probes. Journal of the American Chemical Society. 135 (2), pp. 703-709. https://doi.org/10.1021/ja307926g
First Self-Adjuvant Multicomponent Potential Vaccine Candidates by Tethering of Four or Eight MUC1 Antigenic Immunodominant PDTRP Units on a Calixarene Platform: Synthesis and Biological Evaluation
Geraci, Corrada, Consoli, Grazia M. L., Granata, Giuseppe, Galante, E., Palmigiano, Angelo, Pappalardo, Maria, Di Puma, Salvatore D. and Spadaro, Angelo 2013. First Self-Adjuvant Multicomponent Potential Vaccine Candidates by Tethering of Four or Eight MUC1 Antigenic Immunodominant PDTRP Units on a Calixarene Platform: Synthesis and Biological Evaluation. Bioconjugate Chemistry. 24 (10), pp. 1710-1720. https://doi.org/10.1021/bc400242y
Development of Purine-Derived18F-Labeled Pro-drug Tracers for Imaging of MRP1 Activity with PET
Galante, E., Okamura, Toshimitsu, Sande, Kerstin, Kikuchi, Tatsuya, Okada, Maki, Zhang, Ming-Rong, Robson, Mathew, Badar, Adam, Lythgoe, Mark, Koepp, Matthias and Årstad, Erik 2014. Development of Purine-Derived18F-Labeled Pro-drug Tracers for Imaging of MRP1 Activity with PET. Journal of Medicinal Chemistry. 57 (3), pp. 1023-1032. https://doi.org/10.1021/jm401764a
Silymarin content in Silybum marianum extracts as a biomarker for the quality of commercial tinctures
Pendry, B., Kemp, Virginia, Hughes, Michael J., Freeman, Julia, Nuhu, Hanny K., Sanchez-Medina, Alberto, Corcoran, O. and Galante, E. 2017. Silymarin content in Silybum marianum extracts as a biomarker for the quality of commercial tinctures. Journal of Herbal Medicine. 10, pp. 31-36. https://doi.org/10.1016/j.hermed.2017.07.001
Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography
Sander, K., Galante, E., Gendron, T., Yiannaki, E., Patel, N., Kalber, T. L., Badar, A., Robson, M., Johnson, S. P., Bauer, F., Mairinger, S., Stanek, J., Wanek, T., Kuntner, C., Kottke, T., Weizel, L., Dickens, D., Erlandsson, K., Hutton, B. F., Lythgoe, M. F., Stark, H., Langer, O., Koepp, M. and Årstad, E. 2015. Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography. Journal of Medicinal Chemistry. 58 (15), pp. 6058-6080. https://doi.org/10.1021/acs.jmedchem.5b00652
Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide
Galante, E., Schoultz, Bent, Koepp, Matthias and Årstad, Erik 2013. Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide. Molecules. 18 (5), pp. 5335-5347. https://doi.org/10.3390/molecules18055335